Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck



Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products.


For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability.


Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences.


Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products.

Graphical abstract

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Fig. 1
Fig. 2
Fig. 3
Fig. 4





Active pharmaceutical ingredient


Biopharmaceutical classification system






Clinical endpoint studies


Confidence intervals






Critical quality attributes


Coefficient of variation




European Medicine Agency




Storage modulus


Loss Modulus




Hierarchical cluster analysis


High performance liquid chromatography


In vitro permeation testing


In vitro release rate


In vitro release testing


Linear viscoelastic region


Molecular weight




Non-steroid anti-inflammatory drugs


Phosphate buffered ased saline


Principal component analysis

Q final point:

Cumulative amount of drug released at the end of IVRT

Q initial point:

Cumulative amount of drug released in the beginning of IVRT


Statistical significance




Topical generic product


US Food and Drug Administration


United States Pharmacopeia


Vertical diffusion cell


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Margarida Miranda acknowledges the PhD grant PD/BDE/135075/2017 assigned by FCT (Fundação para a Ciência e Tecnologia, Portugal) and Laboratórios Basi from Drugs R&D Doctoral Program. Tânia Cova also acknowledges the Junior Research grant CEECIND/00915/2018 assigned by FCT. The authors also acknowledge the Coimbra Chemistry Centre, supported by FCT, through the Project UID/QUI/00313/2020.

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Miranda, M., Cova, T., Augusto, C. et al. Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck. Pharm Res 37, 218 (2020). https://doi.org/10.1007/s11095-020-02911-y

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  • batch variability
  • EMA
  • IVRT
  • Rheology
  • topical products